We propose to use a strategy based on the generation and phenotypic analysis of congenic recombinants to identify SLE susceptibility genes in NZM2410. During the previous grant period, we established the feasibility of this approach via our analysis of the Sle1 interval. We have four specific aims: Specific aim 1: To identify Sle1a and Sle1b in the Sle1 gene cluster. We delineate a cluster of susceptibility genes in the Slel1 interval, each expressing a subset of the component phenotypes associated with "Sle1"in B6.NZMc1. We subsequently created congenic recombinant strains carrying Sle1a/z/z (the lupus susceptibility alleles of NZM2410) on congenic intervals of <0.4 cM and produced YAC and BAC contigs spanning their NZM2410-derived congenic intervals. We now propose to identify each of these by a combination of BAC transgenic rescue and DNA sequence analysis. Specific aim 2: To phenotypically characterize and fine map Sle1d. We determined that fatal lupus nephritis in (B6.NZMcl X NZW)F1 hybrids require a gene(s) located in an approximately 9 cM interval present in the B6.NZM1/206- 152 congenic recombinant. Several issues will be resolved concerning this interesting locus: (1) we will determine the component phenotypes expressed by Sle1d in isolation from Sle1b; 2) we will fine map the location of the GN-mediating disease locus (Sle1d) to <1.0 cM; and 3) we will localize the position of Sle1d to a single YAC in the critical interval via transgenic rescue. Specific aim 3: To delineate the gene(s) B6.NZMc7t, each expressing a component of the autoimmune phenotype of B6.NZMc7. We will use strategies analogous to those described for Sleld to fine map Sle3 and Sle5 into critical intervals of <1 cM and ultimately utilize YAC rescue strategies to localize the genes onto single YACs. Specific aim 4: To assess the candidacy of the human homologous of Sle1a and Sle1b in human Sle. The human homologues of murine candidate genes for Sle1a, Sle1b, and Sle1d identified in Aims !& 2 will be screened by TDT analysis to assess their association with susceptibility in human Sle. These studies will be performed by identifying and tracking the inheritance of single nucleotide polymorphisms (SNPs) within the human homologous. This study will be performed as a collaboration with several established investigators working on the genetics of SLE in humans. The identification of these genes in mouse and subsequently in humans will provide vital insights into the genetic mechanisms responsible fir dysregulating a major biological pathway initiating lupus pathogenesis. The major impact that suppression of Sle1 has on disease in mouse models supports the feasibility of targeting this pathway for therapeutic intervention in SLE.